Highlights from Recent Cancer Literature
Journal: Cancer Research (2017)

Cancer cells derived from mesenchymal tissues or those that have undergone an epithelial-mesenchymal transition (EMT) have been reported to possess cancer stem cell (CSC) properties including resistance to standard therapies, necessitating the establishment of targeted molecular therapies. Bollong and colleagues identify FOXC2-inhibiting vimentin effector 1 (FiVe1) as a selective and irreversible inhibitor of tumor growth and CSC potential in several mesenchymal-transformed breast cancer cell lines expressing FOXC2, a transcription factor linking EMT and stem cell properties in breast cancer. Specifically, FiVe1 triggered vimentin phosphorylation and disrupted filamentous vimentin assembly during metaphase, resulting in mitotic defects and ultimately cell-cycle arrest. Importantly, FiVe1 exhibits similar antitumor growth effects in soft tissue sarcomas, which originate from mesenchymal tissues and express vimentin and for which targeted therapies are currently limited. These data demonstrate that targeting vimentin with compounds such as FiVe1 not only has the potential to selectively antagonize EMT-induced CSCs, but may also have translational promise for treating mesenchymal cancers.Bollong MJ, Pietilä M, Pearson AD, Sarkar TR, Ahmad I, Soundararajan R, et al. A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers. Proc Natl Acad Sci U S A 2017;114:E9903–E9912.Radiotherapy is used to treat almost half of all cancer patients, however, nontargeted effects are often observed. To study radiation-induced nontargeted effects, Ventura and colleagues irradiated mice with a synchrotron X-ray broad beam and a multiplanar microbeam radiotherapy beam. Oxidative-induced clustered DNA lesions, DNA double-strand breaks, apoptosis, and local and systemic immune responses were assessed to understand influences of beam configurations and variations in peak dose and irradiated area in the response of normal tissues outside the irradiated field. Pronounced persistent systemic effects were induced at all radiation settings. A wide variety of unirradiated normal tissues showed elevated levels of oxidatively induced clustered DNA lesions. Elevated apoptotic cell death was observed in out-of-field duodenum under most irradiation conditions. Only low doses increased double-strand breaks. Plasma showed changes in macrophage-derived cytokine, eotaxin, IL10, TIMP1, VEGF, TGFβ1, and TGFβ2. These results might aid in reducing the risk of radiation-related adverse systemic effects.Ventura J, Lobachevsky PN, Palazzolo JS, Forrester H, Haynes NM, Ivashkevich A, et al. Localized synchrotron irradiation of mouse skin induces persistent systemic genotoxic and immune responses. Cancer Res 2017;77:6389–99.Metastasis is a fatal step in cancer progression, with a notable feature that different types of cancer spread to specific organs. The molecular and cellular mechanisms underlying tissue-specific metastases are not completely understood. Zhuang and colleagues utilized breast cancer models that metastasize to lung or bone to identify proteins that regulate organotropism. They show that expression of the Wnt signaling inhibitor, DKK1, correlated inversely with lung metastases and directly with bone metastasis. The abrogation of lung metastasis by DKK1 resulted from decreased expression of the noncanonical Wnt target genes PTSG2 and LTBP1. These genes suppressed immune cell infiltration and limited the bioavailability of TGFβ2 in the lung, which led to a tumor-suppressive microenvironment. In the bone, however, DKK1 inhibited canonical Wnt signaling that led to an increase in osteoclast activity and subsequent release of tumor-promoting TGFβ2 from the bone matrix. The authors provide important insights into mechanisms that govern why particular cancers metastasize to specific organs.Zhuang X, Zhang H, Li X, Cong M, Peng F, Yu J, et al. Differential effects on lung and bone metastasis of breast cancer by Wnt signaling inhibitor DKK1. Nat Cell Biol 2017;19:1274–85.Acute myeloid leukemia (AML) is the most common acute leukemia in adults. New therapeutic options are required given the poor 5-year overall survival of 35%–40% achieved with current treatments. To elucidate the transcriptional circuitry and identify novel AML targets, McKeown and colleagues analyzed the transcriptional landscape of 66 AML patients: enhancers, superenhancers, gene expression, and mutational profiles. Six novel subgroups were identified based on superenhancer profiles, independently of gene mutations. Transcriptional targets of the superenhancers included a subset associated with strong expression of the nuclear receptor retinoic acid receptor α (RARα) not found in normal, nonmalignant CD34 positive myeloblasts. The RARα selective agonist, SY-1425, targeted growth of high-expressing RARα AML cells in vitro and in patient-derived xenografts in vivo. Consistent with SY-1425 acting as an agonist, its effects could be blocked by concurrent treatment with a RARα antagonist. They suggest a model in which RARα undergoes a functional switch from a repressor to an activator upon SY-1425 binding, arresting, and differentiating AML cells.McKeown MR, Corces MR, Eaton ML, Fiore C, Lee E, Lopez JT, et al. Superenhancer analysis defines novel epigenomic subtypes of non-APL AML, including an RARα dependency targetable by SY-1425, a potent and selective RARα agonist. Cancer Discov 2017;7:1136–53.The androgen receptor (AR) drives proliferation and survival in prostatic tissue. Accordingly, maintenance of AR expression in the low androgen environment of androgen deprivation therapy (ADT) is a hallmark of progression to incurable castration-resistant prostate cancer (CRPC). Samaranayake and colleagues asked whether this inappropriate AR activity in the low ligand setting required stress-protective adaptations involved in the emergence and progression of CRPC. They identified an unexpected cytotoxic role for high AR levels in CRPC through induction of oxidative stress and p53 in the androgen-deprived setting. This stress is ostensibly masked by high levels of the redox-protective protein thioredoxin-1 (TRX1). Targeting TRX1 both through shRNA and the TRX1-specific inhibitor PX-12 significantly limited castration-resistant tumor formation. This study points to redox-protective proteins as key therapeutic targets and modulators of AR expression and function.Samaranayake GJ, Troccoli CI, Huynh M, Lyles RDZ, Kage K, Win A, et al. Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer. Nat Commun 2017;8:1204. doi: 10.1038/s41467-017-01269-x.Immune evasion is a hallmark of cancer. McGranahan and colleagues developed a computational tool to determine HLA allele-specific copy number alterations in lung squamous and adenocarcinoma patient samples. HLA loss of heterozygosity (LOH) occurred in 40% of non-small cell lung cancers (NSCLC), suggesting LOH as a prevalent mechanism of immune escape. HLA LOH occurred subclonally during progression and trended toward enrichment in metastases. Moreover, subclones with HLA LOH showed higher nonsynonymous mutational burden and neoantigens than their counterparts that lacked HLA LOH. Importantly, these enriched neoantigens were predicted to bind to the lost HLA alleles. Finally, patient samples harboring HLA LOH were associated with upregulation of cytolytic activity and PD-L1 positivity, indicating strong microenvironmental selection pressures to turn off HLA expression. This study provides a useful tool and highlights HLA LOH as a common feature of NSCLC, facilitating immune evasion and subclonal genome evolution.McGranahan N, Rosenthal R, Hiley CT, Rowan AJ, Watkins TBK, Wilson GA, et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell; Published online October 21, 2017; doi: 10.1016/j.cell.2017.10.001.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.